The AIDS epidemic continues to exact a devastating toll on the health, economic and political infrastructure, and social fabric of communities worldwide. During 2011, almost 2.5 million people became newly infected with HIV bringing the total number of people living with HIV to an estimated 34.0 million. In the same year, almost 1.7 million people died from AIDS, raising the global death toll to over 35 million since the first cases of AIDS were identified in 1981 (UNAIDS and WHO 2011 AIDS Epidemic Update; December 2011). HIV/AIDS has become the fourth biggest cause of global mortality. Over 95 percent of new infections are occurring in developing countries, where increasing numbers of new HIV infections threaten the sustainability of expanded access to HIV treatment. Developing safe and effective HIV prevention technologies that can be made easily accessible in developing countries is, thus, an urgent public health priority.
Epidemiologic data published in the latest UNAIDS report show that women and girls bear a severe and increasingly heavy burden of the HIV epidemic. In Eastern Europe and Central Asia, an estimated 26% of adults living with HIV in 2007 were women aged 15 years or older, compared with 23% in 2001. In sub-Saharan Africa, women comprised 61% of HIV-infected adults, and among young people (aged 15-24 years) the ratio of infection had risen to three women for every man (UNAIDS and WHO 2007 AIDS Epidemic Update; December 2007).
Each year, there are also 80 million unintended pregnancies, and 358,000 women die annually from pregnancy-related complications. More than 200 million women in developing countries lack access to contraception. Accordingly, there is a strong need for developing combination products that can prevent both HIV infection and unintended pregnancy in females.
Unprotected heterosexual intercourse is currently the leading mode of HIV infection and unintended pregnancy among females. Correct and consistent use of latex condoms is one proven method of preventing HIV transmission and unintended pregnancy; however, condoms are widely regarded as inadequate prevention options for women if they are unable to negotiate condom use for fear of abuse or accusations of infidelity. Additionally, women who have sex with men in exchange for gifts or money may be reluctant to use condoms if the men are willing to pay more for sex without a condom. The female condom has been marketed as an alternative barrier method, but this device is relatively costly and requires a certain level of skill, as well as acceptance by the male partner. Developing HIV and pregnancy prevention options that women can use with or without their partner's knowledge is a pressing global concern, especially given the rapidly growing HIV infection rate among women and the absence of an effective vaccine.
Topical microbicides that can be self-administered to the vagina are one such promising alternative. Multiple clinical trials with various microbicides have been completed or are currently underway, most of which involve microbicides in gel formulation delivered via a single use applicator used prior to coitus. In order for a microbicide to be effective, it is essential that it be used correctly. Therefore it is important that a microbicide is acceptable to users, and it is likely that products that can be used less frequently will be more acceptable and will achieve better user adherence. Additionally, combination products that could prevent both HIV transmission and unintended pregnancy would be more acceptable to users.
Vaginal rings that need only be replaced at relatively long intervals may therefore have benefits over other dosage forms that must be used more frequently. Ring-shaped devices for the controlled administration of steroid substances (substantially water-insoluble drugs) into the vagina are known in the art, such as Estring®, Femring® and Nuvaring®. There are two basic types of vaginal rings: reservoir rings and matrix rings.
A reservoir ring comprises a full or partial-length core loaded with the drug substance, which is completely surrounded by a non-medicated sheath. Accordingly, the release of drug substances from such rings is dependent upon permeation (i.e., molecular dissolution and subsequent diffusion) of the core-loaded drug substance through the outer sheath. Release rates can be modified by changing the thickness of the rate-controlling sheath and/or the length of the drug-loaded core. Reservoir rings were developed to provide controlled (that is, constant daily) release rates. The polymeric materials used in the construction of commercial vaginal rings are typically hydrophobic materials, such as silicone elastomer and poly(ethylene-co-vinyl acetate) (PEVA) materials. Alternatively, polyurethane may be used.
To date, no combination therapy intravaginal rings have been successfully developed. Combining different drugs in the same intravaginal ring poses unique challenges, due to the different solubility and target release rates of different drugs. Accordingly, there remains a need for the development of improved intravaginal rings which can be loaded with a combination of antimicrobial drugs to prevent the transmission of HIV, or a combination of an antimicrobial drug and a contraceptive to prevent the transmission of HIV and unintended pregnancy.